The complement system is activated in ocular diseases. FIG. 1 provides a schematic diagram of the two primary pathways of the complement system; the classical pathway and the alternative pathway. The alternative pathway (AP) is activated by pathogens and by foreign or abnormal surfaces (such as drusen) and is capable of rapid self-amplification. Excessive and/or prolonged activation of the AP is believed to be the primary cause of many inflammatory and non-inflammatory pathologies and disorders. Age-related macular degeneration (AMD), diabetic retinopathy, uveitis, retinal fibrosis, hemorrhage, and inflammation in many ocular pathologies and disorders, are caused by AP activation and dysregulation.
The AP consists of complement Factors B, D, and P (Properdin). FIG. 2 provides a schematic diagram of the cytokines and growth factors which are produced as a result of complement system activation. Complement factors C3a and C5a activate immune system cells, and other types of cells, to produce TNF-alpha, VEGF, cytokines, growth factors, and other inflammatory mediators. Upon AP activation, C3b binds Properdin and Factor B, forming the complex PC3bB. Factor D then cleaves the Factor B within the complex. This cleavage of Factor B produces an active convertase which cleaves C3 into more C3b and C3a, thereby perpetuating the formation of additional C3 convertase. Additional molecules of C3b and Bb combine with PC3bBb to form an active C5 convertase which cleaves molecules of C5 into C5b and C5a. The C5b then associates with factors C6, C7, C8 and C9 to form the lytic macromolecule C5b-9 (also known as the Membrane Attack Complex, or “MAC”). MAC lyses cells by penetrating cell membranes. This is one of the known processes by which RPE cells, rods and cones, in the context of AMD and other ocular disorders, become damaged as a result of complement system activation.